Fig. 14.

Pathways of RPE organelles. (A) Apical localization of melanosomes in the RPE depends on the tripartite MYO7A-MYRIP-RAB27A complex (MYRIP, MYO7A and Rab interacting protein). Disruption of this complex leads to microtubule-mediated transport of melanosomes in the RPE cell body. Early and recycling endosomes participate in the transcytosis of the Coxsackie-adenovirus receptor (CAR) and the transferrin receptor (TfR) from the basolateral to the apical surface of the RPE. The RAB11-positive apical recycling endosome participates in transporting semaphorin 4A (SEM4A) to the photoreceptors. Endosomal trafficking is important for protecting the RPE from complement attack; the complement regulatory protein CD59 is recycled rapidly to the apical membrane in healthy RPE. In Stargardt disease, excess cholesterol reroutes CD59 towards lysosomes and makes the RPE susceptible to complement attack. Basal early endosomes (EE) endocytose the membrane attack complex (C5b-9) and sort it towards lysosomal degradation. (B) Apical and basal early endosomes mature into apical and basal multivesicular late endosomes, which release their intraluminal vesicles as exosomes either at the apical or basal surfaces. The position of lysosomes in the RPE determines their function. Perinuclear lysosomes are likely involved in digestion of phagocytosed OS disk membranes; whereas lysosomes near the plasma membrane participate in lysosome exocytosis necessary for membrane repair after complement attack. (C) Phagolysosomal digestion of OS releases fatty acids that are transported to mitochondria. Fatty acid oxidation releases β-hydroxybutyrate (β-HB), which is transported to photoreceptors for energy utilization. Very long chain polyunsaturated fatty acids (VLC-PUFA) products of OS catabolism are transported to peroxisomes. Both mitochondria and the ER participate in peroxisome biogenesis. MCT7, monocarboxylate transporter 7.